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PD-1-Associated Gene Expression Signature of Neoadjuvant Trastuzumab-Treated Tumors Correlates with Patient Survival in HER2-Positive Breast Cancer.

ABSTRACT: The therapeutic HER2-targeting antibody trastuzumab has been shown to elicit tumor immune response in a subset of HER2-positive (HER2+) breast cancer. We performed genomic and immunohistochemical profiling of tumors from eight patients who have completed multiple rounds of neoadjuvant trastuzumabb to identify predictive biomarkers for trastuzumab-elicited tumor immune responses. Immunohistochemistry showed that all tumors had an activated tumor immune microenvironment positive for nuclear NF-?B/p65RelA, CD4, and CD8 T cell markers, but only four out of eight tumors were positive for the PD-1 immune checkpoint molecule, which is indicative of an exhausted immune environment. Exome sequencing showed no specific driver mutations correlating with PD-1 positivity. Hierarchical clustering of the RNA sequencing data revealed two distinct groups, of which Group 2 represented the PD-1 positive tumors. A gene expression signature that was derived from this clustering composed of 89 genes stratified HER2+ breast cancer patients in the TCGA dataset and it was named PD-1-Associated Gene Expression Signature in HER2+ Breast Cancer (PAGES-HBC). Patients with the Group 2 PAGES-HBC composition had significantly more favorable survival outcomes with mortality reduced by 83% (hazard ratio 0.17; 95% CI, 0.05 to 0.60; p = 0.011). Analysis of three longitudinal samples from a single patient showed that PAGES-HBC might be transiently induced by trastuzumab, independent of clonal tumor expansion over time. We conclude that PAGES-HBC could be further developed as a prognostic predictor of trastuzumab response in HER2+ breast cancer patients and be potentially used as an alternative biomarker for anti-PD-1 therapy trials.

SUBMITTER: Hendricks WPD

PROVIDER: S-EPMC6826891 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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PD-1-Associated Gene Expression Signature of Neoadjuvant Trastuzumab-Treated Tumors Correlates with Patient Survival in HER2-Positive Breast Cancer.

Hendricks William P D WPD Briones Natalia N Halperin Rebecca F RF Facista Salvatore S Heaton Paul R PR Mahadevan Daruka D Kim Suwon S

Cancers 20191015 10

The therapeutic HER2-targeting antibody trastuzumab has been shown to elicit tumor immune response in a subset of HER2-positive (HER2+) breast cancer. We performed genomic and immunohistochemical profiling of tumors from eight patients who have completed multiple rounds of neoadjuvant trastuzumabb to identify predictive biomarkers for trastuzumab-elicited tumor immune responses. Immunohistochemistry showed that all tumors had an activated tumor immune microenvironment positive for nuclear NF-κB/ ...[more]

PMID: 31618954

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Project description:BackgroundEarly identification of cardiac dysfunction by non-invasive imaging in HER2-positive breast cancer patients treated with trastuzumab is challenging. In particular multigated acquisition (MUGA) scan, which is most widely used, is unable to detect subclinical cardiac changes. The use of N-terminal pro-brain natriuretic peptide (NT-proBNP), a serum biomarker of myocardial stress, might improve timely diagnosis.MethodsThis prospective, single-center, cohort study included patients with HER2-positive breast cancer who started trastuzumab therapy. Echocardiography was scheduled at regular intervals every 3 months during one year follow-up for cardiac function monitoring. For research purposes, NT-proBNP was determined at the same time points. Trastuzumab-induced cardiotoxicity (TIC) was the primary study endpoint, defined as a left ventricular ejection fraction (LVEF) < 45%, and/or an absolute decline in LVEF > 10% since inclusion, and/or the incidence of a clinical cardiac event.ResultsA total of 135 patients were enrolled between April 2008 and June 2016, with a median age of 54 years (IQR: 47-61). By three-dimensional echocardiography (3DE), the median LVEF at baseline was 62% (IQR: 58-65). At a median of 6 months (IQR: 5-11), 45 patients (33%) reached the study endpoint of TIC. Patients with TIC had a mean change of - 9.5% in LVEF (95% CI -7.2 to - 11.7; p = 0.001) during 1 year of trastuzumab treatment. Both NT-proBNP at baseline (HR 1.04, 95% CI 1.02-1.07; p = 0.003) and LVEF decline during anthracycline treatment prior to the start of trastuzumab (HR 1.16, 95% CI 1.07-1.25; p < 0.001) were independently associated with development of TIC. The level of NT-proBNP during follow-up was associated too with development of TIC (HR 1.06 per 10 pmol/l difference, 95% CI 1.02-1.10; p = 0.008). No steadily or sudden increase in NT-proBNP prior to TIC was observed.ConclusionsNT-proBNP cannot be used as a surrogate monitoring tool for trastuzumab-induced cardiotoxicity in HER2-positive breast cancer patients during the first year of treatment. Patients showing an LVEF decline during anthracycline pre-treatment appeared vulnerable for trastuzumab-induced cardiotoxicity.

Project description:BackgroundTrastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. In a phase 1 dose-finding study, a majority of the patients with advanced HER2-positive breast cancer had a response to trastuzumab deruxtecan (median response duration, 20.7 months). The efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine requires confirmation.MethodsIn this two-part, open-label, single-group, multicenter, phase 2 study, we evaluated trastuzumab deruxtecan in adults with pathologically documented HER2-positive metastatic breast cancer who had received previous treatment with trastuzumab emtansine. In the first part of the study, we evaluated three different doses of trastuzumab deruxtecan to establish a recommended dose; in the second part, we evaluated the efficacy and safety of the recommended dose. The primary end point was the objective response, according to independent central review. Key secondary end points were the disease-control rate, clinical-benefit rate, duration of response and progression-free survival, and safety.ResultsOverall, 184 patients who had undergone a median of six previous treatments received the recommended dose of trastuzumab deruxtecan (5.4 mg per kilogram of body weight). In the intention-to-treat analysis, a response to therapy was reported in 112 patients (60.9%; 95% confidence interval [CI], 53.4 to 68.0). The median duration of follow-up was 11.1 months (range, 0.7 to 19.9). The median response duration was 14.8 months (95% CI, 13.8 to 16.9), and the median duration of progression-free survival was 16.4 months (95% CI, 12.7 to not reached). During the study, the most common adverse events of grade 3 or higher were a decreased neutrophil count (in 20.7% of the patients), anemia (in 8.7%), and nausea (in 7.6%). On independent adjudication, the trial drug was associated with interstitial lung disease in 13.6% of the patients (grade 1 or 2, 10.9%; grade 3 or 4, 0.5%; and grade 5, 2.2%).ConclusionsTrastuzumab deruxtecan showed durable antitumor activity in a pretreated patient population with HER2-positive metastatic breast cancer. In addition to nausea and myelosuppression, interstitial lung disease was observed in a subgroup of patients and requires attention to pulmonary symptoms and careful monitoring. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast01 ClinicalTrials.gov number, NCT03248492.).

Project description:BackgroundOverexpression of human epidermal growth factor receptor 2 (HER2) caused by HER2 gene amplification is a driver in breast cancer tumorigenesis. We aimed to investigate the prognostic significance of manual scoring and digital image analysis (DIA) algorithm assessment of HER2 copy numbers and HER2/CEP17 ratios, along with ERBB2 mRNA levels among early-stage HER2-positive breast cancer patients treated with trastuzumab.MethodsThis retrospective study comprised 371 early HER2-positive breast cancer patients treated with adjuvant trastuzumab, with HER2 re-testing performed on whole tumor sections. Digitized tumor tissue slides were manually scored and assessed with uPath HER2 Dual ISH image analysis, breast algorithm. Targeted ERBB2 mRNA levels were assessed by the Xpert® Breast Cancer STRAT4 Assay. HER2 copy number and HER2/CEP17 ratio from in situ hybridization assessment, along with ERBB2 mRNA levels, were explored in relation to recurrence-free survival (RFS).ResultsThe analysis showed that patients with tumors with the highest and lowest manually counted HER2 copy number levels had worse RFS than those with intermediate levels (HR = 2.7, CI 1.4-5.3, p = 0.003 and HR = 2.1, CI 1.1-3.9, p = 0.03, respectively). A similar trend was observed for HER2/CEP17 ratio, and the DIA algorithm confirmed the results. Moreover, patients with tumors with the highest and the lowest values of ERBB2 mRNA had a significantly worse prognosis (HR = 2.7, CI 1.4-5.1, p = 0.003 and HR = 2.8, CI 1.4-5.5, p = 0.004, respectively) compared to those with intermediate levels.ConclusionsOur findings suggest that the association between any of the three HER2 biomarkers and RFS was nonlinear. Patients with tumors with the highest levels of HER2 gene amplification or ERBB2 mRNA were associated with a worse prognosis than those with intermediate levels, which is of importance to investigate in future clinical trials studying HER2-targeted therapy.

Project description:BackgroundHER2DX is a prognostic and predictive assay in early-stage HER2-positive breast cancer based on clinical features and the expression of 4 gene signatures (immune, proliferation, luminal differentiation and HER2 amplicon), including ERBB2 mRNA levels. Here, we evaluated the ability of HER2DX to predict efficacy of a de-escalated, chemotherapy-free neoadjuvant regimen in HER2-positive/hormone receptor-positive breast cancer.MethodsHER2DX was evaluated on pre-treatment tumour samples from the PerELISA phase II study focused on postmenopausal patients with operable HER2-positive/hormone receptor-positive breast cancer. Patients received 2-weeks of letrozole, and then underwent a re-biopsy for Ki67 evaluation. Patients with endocrine therapy sensitive disease (ESD) (i.e., >20.0% Ki67 relative reduction at week 2) continued letrozole and 5 cycles of trastuzumab and pertuzumab. Primary aim was to test the ability of HER2DX risk-score, HER2DX pCR score and HER2DX ERBB2 mRNA score (as continuous variables and group categories) to predict pathological complete response (pCR) in patients with ESD. Logistic regression and receiver...operator curve (ROC) analysis assessed associations of HER2DX scores with pCR and ESD.FindingsHER2DX was evaluated in 55 patients (86.0%) enrolled in PerELISA and 40 patients (73.0%) had ESD. The pCR rate in patients with ESD was 22.5% (9/40). In this group, HER2DX pCR score and HER2DX ERBB2 mRNA score were significantly associated with pCR (p.ß=.ß0.008 and p.ß=.ß0.003, univariate logistic regression model; area under ROC [AUC].ß=.ß0.803 and 0.896). The pCR rate in low, medium, and high HER2DX pCR score groups was 7.7% (2/26), 46.2% (6/13) and 100.0% (1/1), respectively. The pCR rate in low, medium, and high HER2DX ERBB2 score groups was 0.0% (0/12), 7.7% (1/13) and 53.3% (8/15), respectively. HER2DX pCR score was also significantly associated with Ki-67 response following 2-weeks of letrozole (p.ß=.ß0.002, univariate logistic regression model; AUC.ß=.ß0.775). The rate of ESD in low, medium, and high HER2DX pCR score groups was 89.7% (26/29), 65.0% (13/20) and 16.7% (1/6), respectively.InterpretationHER2DX predicts response following neoadjuvant letrozole in combination with dual HER2 blockade with trastuzumab and pertuzumab in early-stage HER2-positive/hormone receptor-positive breast cancer.FundingThis study received funding from Reveal Genomics.

Dataset Information

PD-1-Associated Gene Expression Signature of Neoadjuvant Trastuzumab-Treated Tumors Correlates with Patient Survival in HER2-Positive Breast Cancer.

Publications

PD-1-Associated Gene Expression Signature of Neoadjuvant Trastuzumab-Treated Tumors Correlates with Patient Survival in HER2-Positive Breast Cancer.

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